This application addresses Broad Challenge Area (15): Translational Science and Specific Challenge Topic, 15-MH-109: Prefrontal cortex regulation of higher brain function and complex behaviors. The goal of this project is to understand the neural mechanisms that underlie active maintenance in working memory (WM). WM is a core component of most domains of higher cognition and is critically important for executive control. WM dysfunction is thought to play a major role in the cognitive impairments seen in a wide-range of disorders, including ADHD, Alzheimer's disease, and most prominently, schizophrenia. Progress in understanding the neuronal mechanisms underlying normal and pathological WM function would constitute a major advance in basic science, and will serve as a launch pad for studies in clinical populations, such as patients with schizophrenia, for which WM dysfunction is thought to be a major determinant of more widespread cognitive impairment. Our approach is to conduct directly matched imaging experiments in humans and non-human primates using an identical long-duration memory task in both species, and then to conduct multi-unit recording in monkeys again using the same task. Critically, these studies will be designed to provide detailed information regarding the neural mechanisms that result in the decay of stored information over time (i.e., WM delay), and how this translates into behavioral change. Leverage on these issues will be provided by asking which neurons, circuits, and areas have activity that is correlated with the normal loss of stored WM content over time, and/or correlated with the induced perturbations that result from pharmacologic interventions. We will test whether human and non-human primates show similar neuronal patterns in this regard, and we will use multi-unit recording to test specific hypotheses derived from computational models of attractor networks. Our multi- species, multi-method approach will bridge the gap between computational models, single unit recording studies in non-human primates, and human neuroimaging data. By forming this bridge, we will greatly advance our understanding of the mechanisms of working memory in human cognition. Working memory is a high level function that is absolutely critical to normal cognitive function, and is often disturbed in psychiatric illness. We will investigate the normal and pathological function of spatial working memory in the monkey using a variety of methodologies, and then test the relevance of what we have learned in humans using imaging experiments. The result will be a more principled approach to pharmacologic and other therapies for psychiatric illness.